This research program develops novel tools and methods for high-throughput, real-time analysis of brain activation data, harnessing the power of real-time fMRI (rtfMRI) analysis to allow novel types of cognitive interventions in the investigation and treatment of depression. Our group has demonstrated that rtfMRI-based training enables subjects to learn control over activation of anatomically-localized brain regions, leading to reductions in disease symptoms, including pain and depressive symptoms. These investigations further the NIH mission by advancing understanding of distributed brain mechanisms of depression and by definitively testing a novel therapeutic modality for alleviating a condition which is responsible for substantial human suffering and healthcare cost. This research program will develop novel high-throughput analysis tools that directly enable new methods for cognitive interventions based on rtfMRI-based training. This research will conduct a randomized, controlled, clinical trial of this novel investigative therapeutic technology and methods for treating depression in patients refractory to prior treatment modalities. Decreasing depressive symptoms, and improving control over mood are the initial clinical targets. Phase I: 1) Demonstrate feasibility and efficacy of tasks for cognitive control over mood in depressive patients; 2) Identify brain regions with activations associated with cognitive control over mood in depressive patients. Phase II: 1) Conduct a double-blind, sham-controlled clinical trial of long-term repetitive rtfMRI-based training in depressive patients, 2) Demonstrate enhanced modulation of brain region activation in depressive patients using rtfMRI, and 3) Demonstrate decreased depressive symptoms and increased control over mood following rtfMRI training.